PROJECT SUMMARY With 10 million incident cases and 1.5 million deaths every year, tuberculosis (TB) remains one of the world's deadliest communicable diseases, and constitutes a significant burden on resource-limited countries. Increasing emergence of drug-resistant Mycobacterium tuberculosis (M.tb) strains calls for the development of new and improved treatment options. M.tb persists within its host by using a plethora of complex strategies to modify both its intracellular and local tissue environment that facilitates its survival. Recent efforts have therefore focused on host-directed therapies (HDT) that modulate immune responses to M.tb in favor of the host. Due to the fact that the drug pipeline for TB drugs is sparse, there has also been a resurgence of interest in repurposing drugs that are already FDA-approved. We recently found that pyrazinamide (PZA), an important component of standard TB therapy, inhibits the host enzyme Poly(ADP-ribose) Polymerase-1 (PARP-1), a key immune regulator required for tumor necrosis factor alpha (TNF-?) production and NF-?B target gene expression. PARP- 1 activation is prolonged and sustained in pathophysiological conditions such as cancers and chronic inflammations. Therapeutic inhibition of PARPs is therefore being pursued as a promising anti-cancer and anti- inflammatory strategy. Although a direct role of PARP-1 in the pathology of TB is not yet fully established, the structure of PZA is similar to nicotinamide (NAM), a well-known PARP inhibitor. This proposal therefore aims to determine the role of PARP-1 in the pathogenesis of TB and to test the efficacy of FDA-approved PARP-1 inhibitors olaparib, rucaprib and niraparib, as well as talazoparib which is currently in clinical trials, in mouse models of TB. Results from the proposed study will help to determine if PARP-1 inhibition presents a viable but unexplored strategy to improving the treatment of TB. A better understanding of the role of PARP-1 and the mechanism of inhibition by PZA in M.tb infection promises new insight into pathogenesis of TB and disease control and could lead to other new therapies for the treatment of drug-susceptible as well as drug-resistant strains of M.tb.